Lithium reduced neural progenitor apoptosis in the hippocampus and ameliorated functional deficits after irradiation to the immature mouse brain.

MedLine Citation:

PMID:
22800605
Owner:
NLM
Status:
Publisher

Abstract/OtherAbstract:

Lithium was recently shown to inhibit apoptosis and promote survival of neural progenitor cells after hypoxia-ischemia in the immature rat brain. Our aim was to evaluate the effects of lithium on cell death and proliferation in the hippocampus after irradiation (IR) to the immature brain. Male mice were injected with 2mmol/kg lithium chloride i.p. on postnatal day 9 (P9) and additional lithium injections, 1mmol/kg, were administered at 24h intervals for up to 7days. BrdU was injected 4hours after lithium injections on P9 and P10. The left hemisphere received a single dose of 8Gy (MV photons) on P11. The animals were euthanized 6h or 7weeks after IR. The number of BrdU-labeled cells in the subgranular zone (SGZ) of the granule cell layer (GCL) 6h after IR was 24% higher in the lithium-treated mice. The number of proliferating, phospho-histone H3-positive cells in the SGZ 7weeks after IR was 59% higher in the lithium group, so the effect was long-lasting. The number of apoptotic cells in the SGZ 6h after IR was lower in the lithium group, as judged by 3 different parameters, pyknosis, staining for active caspase-3 and TUNEL. Newly formed cells (BrdU-labeled 1 or 2days before IR) showed the greatest degree of protection, as judged by 50% fewer TUNEL-positive cells, whereas non-BrdU-labeled cells showed 38% fewer TUNEL-positive cells 6h after IR. Consequently, the growth retardation of the GCL was less pronounced in the lithium group. The number and size of microglia in the DG were also lower in the lithium group, indicating reduced inflammation. Learning was facilitated after lithium treatment, as judged by improved context-dependent fear conditioning, and improved place learning, as judged by assessment in the IntelliCage platform. In summary, lithium administration could decrease IR-induced neural progenitor cell apoptosis in the GCL of the hippocampus and ameliorate learning impairments. It remains to be shown if lithium can be used to prevent the debilitating cognitive late effects seen in children treated with cranial radiotherapy.

Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden; Department of Pediatrics, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China.